POPULATION
PHARMACOKINETICS
Sireesha P
L- 5
POPULATION PHARMACOKINETICS
The study of the sources and correlates
the variability in drug concentrations and
effects among individuals who are the target
population receiving clinically relevant doses of
a drug of interest.
…..
popPK aim to identify and quantify sources
of variability in drug concentration in the
patient population
Associations between patient characteristics
and differences in pharmacokinetics can then
be used to customize pharmacotherapy, such
as the safe use of metformin in patients with
renal impairment
INTRODUCTION
Certain patient characteristics, such as
age, body weight, comorbidity and co-
medication, can alter the
pharmacokinetic parameters of a drug.
Population pharmacokinetics seeks to
assess the extent of the variability of
these parameters among a patient
population and to identify the factors that
are responsible for such variability.
Definition
Population Pharmacokinetics is the study of
variability in drug concentrations within a
patient population receiving clinically
relevant doses of a drug of interest.
POPULATION PHARMACOKINETICS INCLUDES:
Assessment of global variability of the
plasma drug concentration profile in a
patient population.
Allocation of this variability to
pharmacokinetic parameters (e.g. variability
of clearance, bioavailability, etc).
Explanation of variability by identifying
factors of demographic, pathophysiological,
environmental, or concomitant drug-related
origin that may influence the
pharmacokinetic parameters.
Quantitative estimation of the magnitude of
the unexplained variability in the patient
population.
CLINICAL IMPLICATIONS
Population pharmacokinetics in the drug
development process helps identify differences in
drug safety and efficiency among population
subgroups.
The mean values of pharmacokinetic parameters
allow the elaboration of the standard dosage
regimen of the drug.
Variability that is due to influential factors leads to
dosage adaptation proposed for patient subsets.
Unexplained variability reflects the reproducibility
of pharmacokinetics.
This is important because the efficacy and safety
of a drug may decrease as unexplained variability
increases.
…CONT
The current interest in population
pharmacokinetics stems from the concern that
the pharmacokinetics of new drugs are not
studied in relevant populations, that is patients
likely to receive the drug, at an early enough
stage in the drug development program. In
particular the FDA (Temple, 1983, 1985) and
others (Abernathy & Azarnoff, 1990) are
concerned that the pharmacokinetics of a new
drug should be studied in elderly populations 'so
that physicians will have sufficient information to
use drugs properly in their older patients'
…CONT
To date most population pharmacokinetic
studies have been carried out within a
clinical setting (Whiting et al., 1986).
One major aim of these studies has been
to establish guidelines for the adjustment
of dosage regimens to be used together
with Therapeutic Drug Monitoring
(Sheiner & Beal, 1982; Vozeh & Steiner,
1987).
…CONT
Using the information provided by the popPK
model, appropriate dosages can be selected
for a given population or subgroup.
NON-POPULATION PHARMACOKINETICS
POPULATION
PHARMACOKINETICS
POPULATION PK IN DRUG
DEVELOPMENT
Population PK modeling and simulation can
help drive decision making at all stages of
drug development (
model-based drug development).
APPLICATION OF POPULATION PK
ANALYSIS
The Application of Population PK Analysis in
Drug Development
Selecting Dosing Regimens To Be Tested in
Clinical Trials
Deriving Sample Size and Sampling Scheme
Requirements to Facilitate the Reliable
Estimation of Covariate Effects
Deriving Exposure Metrics for Conducting
Exposure-Response Analysis
Pediatric Study Designs
….
pediatric study designs
Specific Populations
Drug-Drug Interactions
data used for population pk analysis
Study Subjects and Covariates
PK Sampling Schedule
data analysis
Preliminary Examination of the Data
Model Development
Model Validation
Simulations Based on Population PK Models
…..
labeling based on the results of population
PK analysis
population PK study reporting
APPLICATION OF POPULATION PHARMACOKINETIC
MODELS
Population pharmacokinetic methods are an
emerging and important part of drug
development including preclinical studies,
clinical trials and postmarketing surveillance.
There are excellent reviews from the
pharmaceutical industry and regulatory
perspectives, and web-based guidelines from
regulatory agencies.
Studies have involved research and clinical
applications in a wide variety of patients and
conditions including diabetes, clotting disorders,
malignancy, serious infection, apnoea of
prematurity, pregnancy, organ transplantation,
self-poisoning and arthritis.
SPECIAL PATIENT POPULATIONS
Renal Disease: same hepatic metabolism,
same/increased volume of distribution and
prolonged elimination therefore↑ dosing
interval
Hepatic Disease: same renal elimination,
same/increased volume of distribution, slower
rate of enzyme metabolism therefore ↓dosage,
↑ dosing interval
Cystic Fibrosis Patients: increased metabolism/
elimination, and larger volume of distribution
therefore ↑ dosage, ↓ dosage interval
Pediatrics
DISADVANTAGES
Complex methodology
o Might require simulations (optimal sampling
times); stepwise refinement of model during
study „
o Statistical models not trivial „
o Expensive software with steep learning curve
„
Time consuming „
…..CONT
Validation might require multiple studies
Cost/Benefit ratio
o Unclear beforehand whether the model will
give more than a trivial result (like:
concentrations depend on body weight)
SOFTWARE
NONMEM 7.3
Phoenix/NLME 1.3
Monolix 4.2
SimBiology for MATLAB
PopKinetics for SΛΛM II
Kinetica 5.0 zShareware
Pmetrics for R
EXAMPLES OF SPARSE BLOOD SAMPLING
POP PK STUDIES
the use of population pharmacokinetics to
develop a dosage nomogram for caffeine in
the treatment of infants with apnoea of
prematurity
Another example is safely prescribing
metformin for patients with impaired renal
function
Studies have involved research and clinical
applications in a wide variety of patients and
conditions including diabetes, clotting
disorders, malignancy, serious infection,
apnoea of prematurity, pregnancy, organ
transplantation, self-poisoning and arthritis.
REFERENCE
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